Exforge HCT

CLINICAL PHARMACOLOGY

Mechanism Of Action

The active ingredients of
Exforge HCT target 3 separate mechanisms involved in blood pressure regulation.
Specifically, amlodipine blocks the contractile effects of calcium on cardiac
and vascular smooth muscle cells; valsartan blocks the vasoconstriction and
sodium retaining effects of angiotensin II on cardiac, vascular smooth muscle,
adrenal and renal cells; and hydrochlorothiazide directly promotes the
excretion of sodium and chloride in the kidney leading to reductions in
intravascular volume. A more detailed description of the mechanism of action of
each individual component follows.

Amlodipine

Amlodipine is a dihydropyridine
calcium channel blocker that inhibits the transmembrane influx of calcium ions
into vascular smooth muscle and cardiac muscle. Experimental data suggest that
amlodipine binds to both dihydropyridine and nondihydropyridine binding sites.
The contractile processes of cardiac muscle and vascular smooth muscle are
dependent upon the movement of extracellular calcium ions into these cells
through specific ion channels. Amlodipine inhibits calcium ion influx across
cell membranes selectively, with a greater effect on vascular smooth muscle
cells than on cardiac muscle cells. Negative inotropic effects can be detected in
vitro but such effects have not been seen in intact animals at therapeutic
doses. Serum calcium concentration is not affected by amlodipine. Within the
physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its
kinetic interaction with the calcium channel receptor is characterized by a
gradual rate of association and dissociation with the receptor binding site,
resulting in a gradual onset of effect.

Amlodipine is a peripheral
arterial vasodilator that acts directly on vascular smooth muscle to cause a
reduction in peripheral vascular resistance and reduction in blood pressure.

Valsartan

Angiotensin II is formed from
angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE,
kininase II). Angiotensin II is the principal pressor agent of the
renin-angiotensin system, with effects that include vasoconstriction,
stimulation of synthesis and release of aldosterone, cardiac stimulation, and
renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and
aldosterone-secreting effects of angiotensin II by selectively blocking the
binding of angiotensin II to the AT1 receptor in many tissues, such as vascular
smooth muscle and the adrenal gland. Its action is therefore independent of the
pathways for angiotensin II synthesis.

There is also an AT2 receptor
found in many tissues, but AT2 is not known to be associated with
cardiovascular homeostasis. Valsartan has much greater affinity (about
20000-fold) for the AT1 receptor than for the AT2 receptor. The increased
plasma levels of angiotensin following AT1 receptor blockade with valsartan may
stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is
essentially inactive with an affinity for the AT1 receptor about one-200th that
of valsartan itself.

Blockade of the
renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of
angiotensin II from angiotensin I, is widely used in the treatment of
hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a
reaction also catalyzed by ACE. Because valsartan does not inhibit ACE
(kininase II), it does not affect the response to bradykinin. Whether this
difference has clinical relevance is not yet known. Valsartan does not bind to
or block other hormone receptors or ion channels known to be important in
cardiovascular regulation.

Blockade of the angiotensin II
receptor inhibits the negative regulatory feedback of angiotensin II on renin
secretion, but the resulting increased plasma renin activity and angiotensin II
circulating levels do not overcome the effect of valsartan on blood pressure.

Hydrochlorothiazide

Hydrochlorothiazide is a
thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte
reabsorption, directly increasing excretion of sodium and chloride in
approximately equivalent amounts. Indirectly, the diuretic action of
hydrochlorothiazide reduces plasma volume, with consequent increases in plasma
renin activity, increases in aldosterone secretion, increases in urinary
potassium loss, and decreases in serum potassium. The renin-aldosterone link is
mediated by angiotensin II, so coadministration of an angiotensin II receptor
antagonist tends to reverse the potassium loss associated with these diuretics.

Pharmacodynamics

Exforge HCT has been shown to
be effective in lowering blood pressure. The 3 components of Exforge HCT
(amlodipine, valsartan, hydrochlorothiazide) lower the blood pressure through
complementary mechanisms, each working at a separate site and blocking
different effector pathways. The pharmacodynamics of each individual component
are described below.

Exforge HCT has not been
studied in indications other than hypertension.

Amlodipine

Following administration of
therapeutic doses to patients with hypertension, amlodipine produces
vasodilation resulting in a reduction of supine and standing blood pressures.
These decreases in blood pressure are not accompanied by a significant change
in heart rate or plasma catecholamine levels with chronic dosing. Although the
acute intravenous administration of amlodipine decreases arterial blood
pressure and increases heart rate in hemodynamic studies of patients with
chronic stable angina, chronic oral administration of amlodipine in clinical
trials did not lead to clinically significant changes in heart rate or blood
pressures in normotensive patients with angina.

With chronic, once-daily
administration, antihypertensive effectiveness is maintained for at least 24
hours. Plasma concentrations correlate with effect in both young and elderly
patients. The magnitude of reduction in blood pressure with amlodipine is also
correlated with the height of pretreatment elevation; thus, individuals with
moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater
response than patients with mild hypertension (diastolic pressure 90-104 mmHg).
Normotensive subjects experienced no clinically significant change in blood
pressure (+1/-2 mmHg).

In hypertensive patients with
normal renal function, therapeutic doses of amlodipine resulted in a decrease
in renal vascular resistance and an increase in glomerular filtration rate and
effective renal plasma flow without change in filtration fraction or
proteinuria.

As with other calcium channel
blockers, hemodynamic measurements of cardiac function at rest and during
exercise (or pacing) in patients with normal ventricular function treated with
amlodipine have generally demonstrated a small increase in cardiac index
without significant influence on dP/dt or on left ventricular end diastolic
pressure or volume. In hemodynamic studies, amlodipine has not been associated
with a negative inotropic effect when administered in the therapeutic dose
range to intact animals and man, even when coadministered with beta-blockers to
man. Similar findings, however, have been observed in normals or
well-compensated patients with heart failure with agents possessing significant
negative inotropic effects.

Amlodipine does not change
sinoatrial nodal function or atrioventricular conduction in intact animals or
man. In patients with chronic stable angina, intravenous administration of 10
mg did not significantly alter A-H and HV conduction and sinus node recovery
time after pacing. Similar results were obtained in patients receiving
amlodipine and concomitant beta-blockers. In clinical studies in which
amlodipine was administered in combination with beta-blockers to patients with
either hypertension or angina, no adverse effects of electrocardiographic (ECG)
parameters were observed. In clinical trials with angina patients alone,
amlodipine therapy did not alter ECG intervals or produce higher degrees of AV
blocks.

Amlodipine has indications
other than hypertension which are described in its full prescribing information.

Valsartan

Valsartan inhibits the pressor
effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor
effect by about 80% at peak with approximately 30% inhibition persisting for 24
hours. No information on the effect of larger doses is available.

Removal of the negative
feedback of angiotensin II causes a 2-to 3-fold rise in plasma renin and
consequent rise in angiotensin II plasma concentration in hypertensive
patients. Minimal decreases in plasma aldosterone were observed after
administration of valsartan; very little effect on serum potassium was
observed.

Administration of valsartan to
patients with essential hypertension results in a significant reduction of
sitting, supine, and standing systolic blood pressure, usually with little or
no orthostatic change.

Valsartan has indications other
than hypertension which are described in its full prescribing information.

Hydrochlorothiazide

After oral administration of
hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and
lasts about 6 to 12 hours.

Pharmacokinetics

Exforge HCT

Following oral administration
of Exforge HCT in normal healthy adults, peak plasma concentrations of
amlodipine, valsartan and HCTZ are reached in about 6 hours, 3 hours, and 2
hours, respectively. The rate and extent of absorption of amlodipine, valsartan
and HCTZ from Exforge HCT are the same as when administered as individual
dosage forms.

The bioavailability of
amlodipine, valsartan, and HCTZ were not altered when Exforge HCT was
administered with food. Exforge HCT may be administered with or without food.

Amlodipine

Peak plasma concentrations of
amlodipine are reached 6 to 12 hours after administration of amlodipine alone.
Absolute bioavailability has been estimated to be between 64% and 90%. The
apparent volume of distribution of amlodipine is 21 L/kg. Approximately 93% of
circulating amlodipine is bound to plasma proteins in hypertensive patients.

Amlodipine is extensively
(about 90%) converted to inactive metabolites via hepatic metabolism with 10%
of the parent compound and 60% of the metabolites excreted in the urine.

Elimination of amlodipine from
the plasma is biphasic with a terminal elimination half-life of about 30 to 50
hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days
of consecutive daily dosing.

Valsartan

Following oral administration
of valsartan alone peak plasma concentrations of valsartan are reached in 2 to
4 hours. Absolute bioavailability is about 25% (range 10% to 35%).

The steady state volume of
distribution of valsartan after intravenous administration is 17 L indicating
that valsartan does not distribute into tissues extensively. Valsartan is
highly bound to serum proteins (95%), mainly serum albumin.

Valsartan shows biexponential
decay kinetics following intravenous administration with an average elimination
half-life of about 6 hours. The recovery is mainly as unchanged drug, with only
about 20% of dose recovered as metabolites. The primary metabolite, accounting
for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism
studies involving recombinant CYP450 enzymes indicated that the CYP2C9
isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan.
Valsartan does not inhibit CYP450 isozymes at clinically relevant
concentrations. CYP450 mediated drug interaction between valsartan and
coadministered drugs are unlikely because of the low extent of metabolism.

Valsartan, when administered as
an oral solution, is primarily recovered in feces (about 83% of dose) and urine
(about 13% of dose). Following intravenous administration, plasma clearance of
valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of
total clearance).

Hydrochlorothiazide

The estimated absolute
bioavailability of hydrochlorothiazide after oral administration is about 70%.
Peak plasma hydrochlorothiazide concentrations (Cmax) are reached within 2 to 5
hours after oral administration. There is no clinically significant effect of
food on the bioavailability of hydrochlorothiazide.

Hydrochlorothiazide binds to
albumin (40% to 70%) and distributes into erythrocytes. Following oral
administration, plasma hydrochlorothiazide concentrations decline
biexponentially, with a mean distribution half-life of about 2 hours and an
elimination half-life of about 10 hours.

About 70% of an orally administered
dose of hydrochlorothiazide is eliminated in the urine as unchanged drug.

Special Populations

Geriatric: Elderly patients have
decreased clearance of amlodipine with a resulting increase in peak plasma
levels, elimination half-life, and AUC. Exposure (measured by AUC) to valsartan
is higher by 70% and the half-life is longer by 35% in the elderly than in the
young. Limited amount of data suggest that the systemic clearance of
hydrochlorothiazide is reduced in both healthy and hypertensive elderly
subjects compared to young healthy volunteers.

Gender: Pharmacokinetics of
valsartan do not differ significantly between males and females.

Race: Pharmacokinetic
differences due to race have not been studied.

Renal Insufficiency: The pharmacokinetics of
amlodipine are not significantly influenced by renal impairment. There is no
apparent correlation between renal function (measured by creatinine clearance)
and exposure (measured by AUC) to valsartan in patients with different degrees
of renal impairment. Valsartan has not been studied in patients with severe
impairment of renal function (creatinine clearance < 10 mL/min). Valsartan is
not removed from the plasma by hemodialysis.

Hepatic Insufficiency: Patients with hepatic
insufficiency have decreased clearance of amlodipine with resulting increase in
AUC of approximately 40% to 60%. On average, patients with mild-to-moderate chronic
liver disease have twice the exposure (measured by AUC values) to valsartan of
healthy volunteers (matched by age, sex, and weight). [see Use in Special
Populations]

Drug Interactions

Amlodipine

In vitro data in human plasma indicate that amlodipine has no effect
on the protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Cimetidine: Coadministration of
amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

Grapefruit juice: Coadministration of 240
mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20
healthy volunteers had no significant effect on the pharmacokinetics of
amlodipine.

Maalox® (antacid): Coadministration of the
antacid Maalox with a single dose of amlodipine had no significant effect on
the pharmacokinetics of amlodipine.

Sildenafil: A single 100 mg dose of
sildenafil in subjects with essential hypertension had no effect on the
pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were
used in combination, each agent independently exerted its own blood pressure
lowering effect.

Atorvastatin: Coadministration of
multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no
significant change in the steady state pharmacokinetic parameters of
atorvastatin.

Digoxin: Coadministration of
amlodipine with digoxin did not change serum digoxin levels or digoxin renal
clearance in normal volunteers.

Ethanol (alcohol): Single and multiple 10 mg
doses of amlodipine had no significant effect on the pharmacokinetics of
ethanol.

Warfarin: Coadministration of
amlodipine with warfarin did not change the warfarin prothrombin response time.

Simvastatin: Coadministration of
multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77%
increase in exposure to simvastatin compared to simvastatin alone. Limit the
dose of simvastatin in patients on amlodipine to 20 mg daily.

CYP3A4 Inhibitors: Coadministration of a 180
mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive
patients resulted in a 60% increase in amlodipine systemic exposure.
Erythromycin coadministration in healthy volunteers did not significantly
change amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g.,
ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations
of amlodipine to a greater extent.

Hydrochlorothiazide

Drugs that alter
gastrointestinal motility: The bioavailability of thiazide-type diuretics may be
increased by anticholinergic agents (e.g., atropine, biperiden), apparently due
to a decrease in gastrointestinal motility and the stomach emptying rate.
Conversely, pro-kinetic drugs may decrease the bioavailability of thiazide
diuretics.

Cholestyramine: In a dedicated drug interaction
study, administration of cholestyramine 2 hours before hydrochlorothiazide
resulted in a 70% reduction in exposure to hydrochlorothiazide. Further,
administration of hydrochlorothiazide 2 hours before cholestyramine resulted in
35% reduction in exposure to hydrochlorothiazide.

Clinical Studies

Exforge HCT was studied in a
double-blind, active controlled study in hypertensive patients. A total of 2271
patients with moderate to severe hypertension (mean baseline systolic/diastolic
blood pressure was 170/107 mmHg) received treatments of
amlodipine/valsartan/HCTZ 10/320/25 mg, valsartan/HCTZ 320/25 mg,
amlodipine/valsartan 10/320 mg, or HCTZ/amlodipine 25/10 mg. At study
initiation patients assigned to the 2component arms received lower doses of
their treatment combination while patients assigned to the Exforge HCT arm
received 160/12.5 mg valsartan/hydrochlorothiazide. After 1 week, Exforge HCT
patients were titrated to 5/160/12.5 mg
amlodipine/valsartan/hydrochlorothiazide, while all other patients continued
receiving their initial doses. After 2 weeks, all patients were titrated to
their full treatment dose. A total of 55% of patients were male, 14% were 65
years or older, 72% were Caucasian, and 17% were black.

At week 8, the triple
combination therapy produced greater reductions in blood pressure than each of
the 3 dual combination treatments (p < 0.0001 for both diastolic and systolic
blood pressures reductions). The reductions in systolic/diastolic blood
pressure with Exforge HCT were 7.6/5.0 mmHg greater than with valsartan/HCTZ,
6.2/3.3 mmHg greater than with amlodipine/valsartan, and 8.2/5.3 mmHg greater
than with amlodipine/HCTZ (see Figure 1). The full blood pressure
lowering effect was achieved 2 weeks after being on the maximal dose of Exforge
HCT (see Figure 2 and Figure 3). As the pivotal study was an
active-controlled trial, the treatment effects shown in Figures 1, 2, and 3
include a placebo effect of unknown size.

Figure 1: Reduction in Mean
Blood Pressure at Endpoint

Figure 2: Mean Sitting
Diastolic Blood Pressure by Treatment and Week

Figure 3: Mean Sitting
Systolic Blood Pressure by Treatment and Week

A subgroup of 283 patients was
studied with ambulatory blood pressure monitoring. The blood pressure lowering
effect in the triple therapy group was maintained throughout the 24-hour period
(see Figure 4 and Figure 5).

There are no trials of the
Exforge HCT combination tablet demonstrating reductions in cardiovascular risk
in patients with hypertension, but both the amlodipine and hydrochlorothiazide
components and several ARBs, which are the same pharmacological class as the
valsartan component, have demonstrated such benefits.

Last reviewed on RxList: 6/20/2014
This monograph has been modified to include the generic and brand name in many instances.